A Light-Triggered J-Aggregation-Regulated Therapy Conversion: from Photodynamic/Photothermal Therapy to Long-Lasting Chemodynamic Therapy for Effective Tumor Ablation.

Reactive oxygen species (ROS) have become an effective tool for tumor treatment. The combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT) takes advantage of various ROS and enhances therapeutic effects. However, the activation of CDT usually occurs before PDT, which hinders the sustained maintenance of hydroxyl radicals (⋅OH) and reduces the treatment efficiency. Herein, we present a light-triggered nano-system based on molecular aggregation regulation for converting cancer therapy from PDT/photothermal therapy (PTT) to a long-lasting CDT. The ordered J-aggregation enhances the photodynamic properties of the cyanine moiety while simultaneously suppressing the chemodynamic capabilities of the copper-porphyrin moiety. Upon light irradiation, Cu-PCy JNPs demonstrate strong photodynamic and photothermal effects. Meanwhile, light triggers a rapid degradation of the cyanine backbone, leading to the destruction of the J-aggregation. As a result, a long-lasting CDT is sequentially activated, and the sustained generation of ⋅OH is observed for up to 48 hours, causing potent cellular oxidative stress and apoptosis. Due to their excellent tumor accumulation, Cu-PCy JNPs exhibit effective in vivo tumor ablation through the converting therapy. This work provides a new approach for effectively prolonging the chemodynamic activity in ROS-based cancer therapy.

Cyclin B1: A potential prognostic and immunological biomarker in pan-cancer.

Cyclin B1 (CCNB1) encodes a regulatory protein essential for the regulation of cell mitosis, particularly in controlling the G2/M transition phase of the cell cycle. Current research has implicated CCNB1 in the progression of various types of cancer, including gastric cancer, breast cancer, and non-small cell lung cancer. In this study, we conducted a pan-cancer analysis of CCNB1 to investigate its prognostic significance and immunological aspects. Our comprehensive investigation covered a wide range of analyses, including gene expression, promoter methylation, genetic alterations, immune infiltration, immune regulators, and enrichment studies. We utilized multiple databases and tools for this purpose, such as The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, the Human Protein Atlas (HPA), the University of Alabama at Birmingham CANcer data analysis Portal (UALCAN), the Gene Expression Profiling Interactive Analysis (GEPIA), the DNA Methylation Interactive Visualization Database (DNMIVD), the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), Sangerbox, and cBioPortal. Data analyses were executed using GraphPad Prism software, R software, and various online tools. Our findings demonstrated a significant increase in CCNB1 expression across 28 cancer types. Elevated CCNB1 expression correlated with decreased overall survival (OS) in 11 cancer types and disease-free survival (DFS) in 12 cancer types. Additionally, DNA promoter methylation levels were significantly decreased in 14 cancer types. Furthermore, the study verified a significant association between CCNB1 expression and immune infiltration, immune modulators, microsatellite instability (MSI), and tumor mutational burden (TMB). Enrichment analysis indicated that CCNB1 is involved in multiple cellular pathways. Collectively, our results suggested that CCNB1 has the potential to serve as a valuable prognostic biomarker and may be a promising target for immunotherapy in various cancer types.

SIRGs score may be a predictor of prognosis and immunotherapy response for esophagogastric junction adenocarcinoma.

Background: Esophagogastric junction adenocarcinoma (EGJA) is a special malignant tumor with unknown biological behavior. PD-1 checkpoint inhibitors have been recommended as first-line treatment for advanced EGJA patients. However, the biomarkers for predicting immunotherapy response remain controversial. Methods: We identified stromal immune-related genes (SIRGs) by ESTIMATE from the TCGA-EGJA dataset and constructed a signature score. In addition, survival analysis was performed in both the TCGA cohort and GEO cohort. Subsequently, we explored the differences in tumor-infiltrating immune cells, immune subtypes, immune-related functions, tumor mutation burden (TMB), immune checkpoint gene expression, immunophenoscore (IPS) between the high SIRGs score and low SIRGs score groups. Finally, two validation cohorts of patients who had accepted immunotherapy was used to verify the value of SIRGs score in predicting immunotherapy response. Results: Eight of the SIRGs were selected by LASSO regression to construct a signature score (SIRGs score). Univariate and multivariate analyses in the TCGA and GEO cohort suggested that SIRGs score was an independent risk factor for the overall survival (OS) and it could increase the accuracy of clinical prediction models for survival. However, in the high SIRGs score group, patients had more immune cell infiltration, more active immune-related functions, higher immune checkpoint gene expression and higher IPS-PD1 and IPS-PD1-CTLA4 scores, which indicate a better response to immunotherapy. The external validation illustrated that high SIRGs score was significantly associated with immunotherapy response and immune checkpoint inhibitors (ICIs) can improve OS in patients with high SIRGs score. Conclusion: The SIRGs score may be a predictor of the prognosis and immune-therapy response for esophagogastric junction adenocarcinoma.

[Anti-tumor effect of Huaier extract supernatant on human gastric cancer HGC-27 and MGC-803 cells].

The purpose of this study was to investigate the effect of Huaier extract supernatant(HES) on the proliferation, apoptosis, autophagy, and migration of human gastric cancer HGC-27 and MGC-803 cells and its molecular mechanisms. The main components in HES were preliminarily analyzed by high-performance liquid chromatography-mass spectrometry(HPLC-MS). Methyl thiazolyl tetrazolium(MTT) assay, colony formation assay, and 5-ethynyl-2'-deoxyuridine(EdU) staining assay were used to explore the effect of HES on the proliferation of human gastric cancer HGC-27 and MGC-803 cells. Hoechst staining and flow cytometry assay were used to determine the effect of HES on apoptosis of human gastric cancer HGC-27 and MGC-803 cells. Acridine orange staining and cell scratch assay were used to determine the effect of HES on autophagy and migration of human gastric cancer HGC-27 and MGC-803 cells, respectively. Western blot was used to investigate the regulatory effect of HES on the expression levels of proteins related to apoptosis, epithelial-mesenchymal transition(EMT), and signaling pathways in human gastric cancer HGC-27 and MGC-803 cells. The results showed that HES mainly contained some components with high polarities. HES significantly reduced the cell viability of human gastric cancer cells in a dose-and time-dependent manner. The IC_(50 )values after 48 h of HES treatment in human gastric cancer HGC-27 and MGC-803 cells were 7.56 and 10.77 g·L~(-1), respectively. Meanwhile, HES inhibited the colony-forming ability and short-term proliferation of human gastric cancer cells. The apoptosis rates of HGC-27 and MGC-803 cells treated with 8 g·L~(-1) HES for 72 h were 62.13%±8.92% and 54.50%±3.26%, respectively. HES also promoted autophagy in human gastric cancer cells and impaired their migration ability in vitro. Moreover, HES up-regulated the cleavage of the apoptosis marker poly ADP-ribose polymerase(PARP) and the protein expression level of the epithelial cell marker E-cadherin, and down-regulated the protein levels of phosphorylated-mammalian target of rapamycin(p-mTOR), phosphorylated-S6(p-S6), and phosphorylated-extracellular signal-regulated kinase(p-ERK) in human gastric cancer cells. Therefore, HES is one of the effective anti-tumor components of Huaier, which inhibits the proliferation and migration of human gastric cancer cells, and induces apoptosis and autophagy. Moreover, the mTOR signal and ERK signal may be involved in the anti-gastric cancer effect of HES. This study provides novel references for the in-depth research and clinical application of Huaier. It is also of great significance to promote the scientific development and utilization of Huaier.

Polyketide pesticides from actinomycetes.

Natural product derived pesticides have increased in popularity worldwide because of their high efficacy, eco-friendly nature and favorable safety profile. The development of polyketide pesticides from actinomycetes reflects this increase in popularity in the past decades. These pesticides, which include avermectins, spinosyns, polynactins, tetramycin and their analogues, have been successfully applied in crop protection. Moreover, the advance of biotechnology has led to continuous improvement in the discovery and production processes. In this review, we summarize these polyketide pesticides, their activities and provide insight into their development. We also discuss engineering strategies and the current status of industrial production for these pesticides. Given that actinomycetes are known to produce a wide range of bioactive secondary metabolites, the description of pesticide development and high yield strain improvement presented herein will facilitate further development of these valuable polyketide pesticides from actinomycetes.

[Research progress on anti-tumor effect of Chinese dragon's blood].

As a traditional Chinese medicine, Chinese dragon's blood has multiple effects, such as activating blood to remove blood stasis, softening and dispelling stagnation, astringent and hemostasis, clearing swelling and relieving pain, regulating menstruation and rectifying the blood, so it is called "an effective medicine of promoting blood circulation". It has been widely used clinically to treat a variety of diseases. With the further research on Chinese dragon's blood, its anti-tumor medicinal value is gradually emerging. Modern pharmacological studies have shown that Chinese dragon's blood exerts anti-tumor effects mainly by inhibiting cell proliferation, inducing apoptosis, inducing DNA damage and cell cycle arrest, inducing senescence and autophagy of tumor cells, inhibiting metastasis and angiogenesis, as well as reversing multidrug resistance. This article focuses on the research progress on anti-tumor effects of Chinese dragon's blood extract and its chemical components, with a view to provide new references for the in-depth research and reasonable utilization of Chinese dragon's blood.

p39-associated Cdk5 activity regulates dendritic morphogenesis.

Dendrites, branched structures extending from neuronal cell soma, are specialized for processing information from other neurons. The morphogenesis of dendritic structures is spatiotemporally regulated by well-orchestrated signaling cascades. Dysregulation of these processes impacts the wiring of neuronal circuit and efficacy of neurotransmission, which contribute to the pathogeneses of neurological disorders. While Cdk5 (cyclin-dependent kinase 5) plays a critical role in neuronal dendritic development, its underlying molecular control is not fully understood. In this study, we show that p39, one of the two neuronal Cdk5 activators, is a key regulator of dendritic morphogenesis. Pyramidal neurons deficient in p39 exhibit aberrant dendritic morphology characterized by shorter length and reduced arborization, which is comparable to dendrites in Cdk5-deficient neurons. RNA sequencing analysis shows that the adaptor protein, WDFY1 (WD repeat and FYVE domain-containing 1), acts downstream of Cdk5/p39 to regulate dendritic morphogenesis. While WDFY1 is elevated in p39-deficient neurons, suppressing its expression rescues the impaired dendritic arborization. Further phosphoproteomic analysis suggests that Cdk5/p39 mediates dendritic morphogenesis by modulating various downstream signaling pathways, including PI3K/Akt-, cAMP-, or small GTPase-mediated signaling transduction pathways, thereby regulating cytoskeletal organization, protein synthesis, and protein trafficking.

Supraciliary Incision as a New Double-Eyelid Approach for Asian Patients: Clinical Experience of 528 Cases.

BACKGROUND: The double-eyelid operation is the most requested cosmetic surgery in Asians. The incision is usually located at the pretarsal skin 6 mm to 8 mm above palpebral margin. The purpose of this paper is to report a novel approach of double-eyelid operation through a supraciliary incision (SCI). METHODS: Three transverse curved lines were drawn on the upper lid skin. The location of line 1 (SCI) was 1.5 mm above the eyelash, line 2 according to the amount of redundant skin excised and line 3 at 3 mm to 4 mm above line 2. After the incisions were made between line 1 and line 2, the subcutaneous dissection is carried out over 5 mm the line 3. Then, the redundant skin and a strip orbicularis oculi muscle were removed to open the orbital septum and to explore underside levator aponeurosis. Along the line 3, the internal buried fixation sutures between dermal tissue and the fusion line of the orbital septum and levator aponeurosis were placed. Finally, the wounds were closed between line 2 and line 1. RESULTS: There were 528 patients who underwent the double-eyelid operation through the supraciliary approach. In long-term follow-up, 288 patients were evaluated at 6 months to 78 months postoperatively. Of those, 266 patients were satisfactory for the result (92.36%) with natural shape and invisible surgical scar. In another 22 patients (7.63%), a revised blepharoplasty was performed in 22 eyelids. CONCLUSION: The double-eyelid surgery using the SCI has several advantages including less visibility of the incision, the protected subdermal vascular network, the intact continuity of the upper eyelid skin, the combination of the SCI and internal dermal buried suture method. The approach can be considered an efficient technique for Asian patients. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Enhanced Tolerance to Methyl Viologen-Mediated Oxidative Stress via AtGR2 Expression From Chloroplast Genome.

Owing to their sessile life habit, plants are continuously subjected to a broad range of environmental stresses. During periods of (a)biotic stresses, reactive oxygen species (ROS) levels can rise excessively, leading to oxidative stress. Glutathione reductase (GR) plays an important role in scavenging the ROS and maintenance of redox potential of the cell during oxidative stress. To enhance ROS scavenging capacity, and hence stress tolerance, the Arabidopsis thalianaGR2 (AtGR2) gene was expressed from the tobacco plastid (chloroplast) genome, the main source of ROS production in plant photosynthetic tissues, in this study. Leaves of transplastomic tobacco plants had about seven times GR activity and 1.5 times total glutathione levels compared to wild type. These transplastomic tobacco plants showed no discernible phenotype and exhibited more tolerance to methyl viologen-induced oxidative stress than wild-type control plants. The results indicate that introducing AtGR2 in chloroplasts is an efficient approach to increase stress tolerance. This study also provides evidence that increasing antioxidant enzyme via plastid genome engineering is an alternative to enhance plant's tolerance to stressful conditions.

Numb confers to inhibit epithelial mesenchymal transition via ß-catenin/Lin28 signaling pathway in breast cancer.

OBJECTIVES: This study aimed to investigate role of Numb in the epithelial mesenchymal transition (EMT) of breast cancer. METHODS: Numb and ß-catenin were inhibited in MCF-7 cells using sh-RNA and overexpressed in T47D cells by pcDNA3.0-Numb, pcDNA3.0-ß-catenin. Cell proliferation, invasion and migration were evaluated using MTT and Transwell assay, respectively. ß-catenin, Lin28, and EMT related markers were determined using qRT-PCR and Western Blotting. RESULTS: Knockdown of Numb significantly promoted the proliferation, invasion and migration of MCF-7 cells, further increased the expression of ß-catenin, Lin28, Snail-1, and N-cadherin, as well as decreased E-cadherin. In T47D cells transfected with pcDNA3.0-Numb, the results were quite the reverse. CONCLUSIONS: Knockdown of Numb could promote the EMT of breast cancer cells via ß-cateni/Lin28 signaling pathway.

Comparison between linear and nonlinear machine-learning algorithms for the classification of thyroid nodules.

BACKGROUND: A key challenge in thyroid carcinoma is preoperatively diagnosing malignant thyroid nodules. The purpose of this study was to compare the classification performance of linear and nonlinear machine-learning algorithms for the evaluation of thyroid nodules using pathological reports as reference standard. METHODS: Ethical approval was obtained for this retrospective analysis, and the informed consent requirement was waived. A total of 1179 thyroid nodules (training cohort, n = 700; validation cohort, n = 479) were confirmed by pathological reports or fine-needle aspiration (FNA) biopsy. The following ultrasonography (US) featu res were measured for each nodule: size (maximum diameter), margins, shape, aspect ratio, capsule, hypoechoic halo, composition, echogenicity, calcification pattern, vascularity, and cervical lymph node status. We analyzed five nonlinear and three linear machine-learning algorithms. The diagnostic performance of each algorithm was compared by using the area under the curve (AUC) of the receiver operating characteristic curve. We repeated this process 1000 times to obtain the mean AUC and 95% confidence interval (CI). RESULTS: Overall, nonlinear machine-learning algorithms demonstrated similar AUCs compared with linear algorithms. The Random Forest and Kernel Support Vector Machines algorithms achieved slightly greater AUCs in the validation cohort (0.954, 95% CI: 0.939-0.969; 0.954 95%CI: 0.939-0.969, respectively) than other algorithms. CONCLUSIONS: Overall, nonlinear machine-learning algorithms share similar performance compared with linear algorithms for the evaluation the malignancy risk of thyroid nodules.

A nomogram for individual prediction of vascular invasion in primary breast cancer.

OBJECTIVES: To explore the feasibility of preoperative prediction of vascular invasion (VI) in breast cancer patients using nomogram based on multiparametric MRI and pathological reports. METHODS: We retrospectively collected 200 patients with confirmed breast cancer between January 2016 and January 2018. All patients underwent MRI examinations before the surgery. VI was identified by postoperative pathology. The 200 patients were randomly divided into training (n = 100) and validation datasets (n = 100) at a ratio of 1:1. Least absolute shrinkage and selection operator (LASSO) regression was used to select predictors most associated with VI of breast cancer. A nomogram was constructed to calculate the area under the curve (AUC) of receiver operating characteristics, sensitivity, specificity, accuracy, positive prediction value (PPV) and negative prediction value (NPV). We bootstrapped the data for 2000 times without setting the random seed to obtain corrected results. RESULTS: VI was observed in 79 patients (39.5%). LASSO selected 10 predictors associated with VI. In the training dataset, the AUC for nomogram was 0.94 (95% confidence interval [CI]: 0.89-0.99, the sensitivity was 78.9% (95%CI: 72.4%-89.1%), the specificity was 95.3% (95%CI: 89.1%-100.0%), the accuracy was 86.0% (95%CI: 82.0%-92.0%), the PPV was 95.7% (95%CI: 90.0%-100.0%), and the NPV was 77.4% (95%CI: 67.8%-87.0%). In the validation dataset, the AUC for nomogram was 0.89 (95%CI: 0.83-0.95), the sensitivity was 70.3% (95%CI: 60.7%-79.2%), the specificity was 88.9% (95%CI: 80.0%-97.1%), the accuracy was 77.0% (95%CI: 70.0%-83.0%), the PPV was 91.8% (95%CI: 85.3%-98.0%), and the NPV was 62.7% (95%CI: 51.7%-74.0%). The nomogram calibration curve shows good agreement between the predicted probability and the actual probability. CONCLUSION: The proposed nomogram could be used to predict VI in breast cancer patients, which was helpful for clinical decision-making.

Development and validation of an ultrasound-based nomogram to improve the diagnostic accuracy for malignant thyroid nodules.

OBJECTIVES: The aim of this study was to develop an ultrasound-based nomogram to improve the diagnostic accuracy of the identification of malignant thyroid nodules. METHODS: A total of 1675 histologically proven thyroid nodules (1169 benign, 506 malignant) were included in this study. The nodules were grouped into the training dataset (n = 700), internal validation dataset (n = 479), or external validation dataset (n = 496). The grayscale ultrasound features included the nodule size, shape, aspect ratio, echogenicity, margins, and calcification pattern. We applied least absolute shrinkage and selection operator (lasso) regression to select the strongest features for the nomogram. Nomogram discrimination (area under the receiver operating characteristic curve, AUC) and calibration were assessed. The nomogram was subjected to bootstrapping validation (1000 bootstrap resamples) to calculate a mean AUC and 95% confidence interval (CI). RESULTS: The nomogram showed good discrimination in the training dataset, with an AUC of 0.936 (95% CI: 0.918-0.953) and good calibration. Application of the nomogram to the internal validation dataset also resulted in good discrimination (AUC: 0.935; 95% CI, 0.915-0.954) and good calibration. The model tested in an external validation dataset demonstrated a lower AUC of 0.782 (95% CI: 0.776-0.789). CONCLUSIONS: This ultrasound-based nomogram can be used to quantify the probability of malignant thyroid nodules. KEY POINTS: • Ultrasound examination is helpful in the differential diagnosis of malignant and benign thyroid nodules. • However, ultrasound accuracy relies heavily on examiner experience. • A less subjective diagnostic model is desired, and the developed nomogram for thyroid nodules showed good discrimination and good calibration.

Advantages with prophylactic PEG-rhG-CSF versus rhG-CSF in breast cancer patients receiving multiple cycles of myelosuppressive chemotherapy: an open-label, randomized, multicenter phase III study.

BACKGROUND: PEG-rhG-CSF reduces neutropenia and improves chemotherapy safety. In China's registration trial (CFDA: 2006L01305), we assessed its efficacy and safety against rhG-CSF, and prospectively explored its value over multiple cycles of chemotherapy. METHODS: In this open-label, randomized, multicenter phase 3 study, breast cancer patients (n = 569) were randomized to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg/d after chemotherapy. The primary endpoints were the incidence and duration of grade 3/4 neutropenia during cycle 1. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia during cycles 2-4, the incidence of febrile neutropenia, and the safety. RESULTS: A once-per-cycle PEG-rhG-CSF at either 100 µg/kg or 6 mg was not different from daily injections of rhG-CSF for either incidence or duration of grade 3/4 neutropenia. Interestingly, a substantial difference was noted during cycle 2, and the difference became bigger over cycles 3-4, reaching a statistical significance at cycle 4 in either incidence (P = 0.0309) or duration (P = 0.0289) favoring PEG-rhG-CSF. A significant trend toward a lower incidence of all-grade adverse events was noted at 129 (68.98%), 142 (75.53%), and 160 (82.47%) in the PEG-rhG-CSF 100 µg/kg and 6 mg and rhG-CSF groups, respectively (P = 0.0085). The corresponding incidence of grade 3/4 drug-related adverse events was 2/187 (1.07%), 1/188 (0.53%), and 8/194 (4.12%), respectively (P = 0.0477). Additionally, PFS in metastatic patients preferred PEG-rhG-CSF to rhG-CSF despite no significance observed by Kaplan-Meier analysis (n = 49, P = 0.153). CONCLUSIONS: PEG-rhG-CSF is a more convenient and safe formulation and a more effective prophylactic measure in breast cancer patients receiving multiple cycles of chemotherapy.

Body mass index (BMI) may be a prognostic factor for gastric cancer with peritoneal dissemination.

BACKGROUND: The aim of this study is to investigate whether body mass index (BMI) is a prognostic factor in gastric cancer patients with peritoneal dissemination. METHODS: This is a retrospective study consisting of 518 patients with a histological diagnosis of gastric cancer with peritoneal dissemination seen at the Sixth Affiliated Hospital of Sun Yat-Sen University and Sun Yat-sen University Cancer Center between January 2010 and April 2014. Patients were followed until December 2015. Chi-square test and Kaplan-Meier survival analysis were used to compare the clinicopathological variables and prognosis. RESULTS: Univariate analyses showed that significant prognostic factors included palliative gastrectomy (p < 0.001), tumor size (p < 0.001), tumor location (p = 0.011), peritoneal seeding grade (p < 0.001), ascites (p = 0.001), serum CEA level (p = 0.002), serum CA19-9 level (p = 0.033), palliative chemotherapy (p < 0.001), and BMI group (p < 0.001). For patients with palliative chemotherapy, univariate analysis revealed that palliative gastrectomy (p < 0.001), tumor size (p = 0.002), tumor location (p = 0.024), peritoneal seeding grade (p = 0.008), serum CEA level (p = 0.041), and BMI group (p < 0.001). Multivariate analysis revealed that BMI was an independent prognostic factor in gastric cancer patients with peritoneal dissemination, especially in patients who received palliative chemotherapy. CONCLUSIONS: BMI is a prognostic factor for patients who have gastric cancer with peritoneal dissemination, especially in those who received palliative chemotherapy.

Nomogram analysis and external validation to predict the risk of lymph node metastasis in gastric cancer.

AIM: To identify risk factors for lymph node metastasis using a nomogram for gastric cancer patients to predict lymph node metastasis. RESULTS: The Chi-square test and the logistic regression showed that the Boarrmann type, preoperative CA199 level, T stage and N stage by CT scan were independent risk factors. The concordance index (C-index) was 0.786 in the internal validation of the Nomogram model. In the external validation, the C-index was 0.809, and the AUC was 0.894. The total accuracy of the prediction was 82.2%, and the false-negative rate was 5.4% with a cut-off value set at 0.109. MATERIALS AND METHODS: The study consisted of 451 patients with a histological diagnosis of gastric cancer with 0 or 1 lymph node metastasis from the Sun Yat-sen University Cancer Center as the development set, and the validation set consisted of 186 gastric cancer patients from the Sixth Affiliated Hospital of Sun Yat-Sen University. A Chi-square test and a logistic regression analysis were used to compare the clinicopathological variables and lymph node metastasis. The C-index and ROC curve were computed for comparisons of the nomogram's predictive ability. CONCLUSIONS: We developed and validated a nomogram to predict lymph node metastasis in gastric cancer before surgery. This nomogram can be broadly applied, even in general hospitals, and is useful for decisions regarding treatment programs for patients.

Cortical regulation of striatal projection neurons and interneurons in a Parkinson's disease rat model.

Striatal neurons can be either projection neurons or interneurons, with each type exhibiting distinct susceptibility to various types of brain damage. In this study, 6-hydroxydopamine was injected into the right medial forebrain bundle to induce dopamine depletion, and/or ibotenic acid was injected into the M1 cortex to induce motor cortex lesions. Immunohistochemistry and western blot assay showed that dopaminergic depletion results in significant loss of striatal projection neurons marked by dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein, molecular weight 32 kDa, calbindin, and µ-opioid receptor, while cortical lesions reversed these pathological changes. After dopaminergic deletion, the number of neuropeptide Y-positive striatal interneurons markedly increased, which was also inhibited by cortical lesioning. No noticeable change in the number of parvalbumin-positive interneurons was found in 6-hydroxydopamine-treated rats. Striatal projection neurons and interneurons show different susceptibility to dopaminergic depletion. Further, cortical lesions inhibit striatal dysfunction and damage induced by 6-hydroxydopamine, which provides a new possibility for clinical treatment of Parkinson's disease.

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells.

The expansion of myeloid-derived suppressor cells (MDSCs) is a common feature of cancer, but its biological roles and molecular mechanism remain unclear. Here, we investigated a molecular link between MDSC expansion and tumor cell metastasis in nasopharyngeal carcinoma (NPC). We demonstrated that MDSCs expanded and were positively correlated with the elevated tumor COX-2 expression and serum IL-6 levels in NPC patients. Importantly, COX-2 and MDSCs were poor predictors of patient disease-free survival (DFS). Knocking down tumor COX-2 expression hampered functional TW03-mediated-MDSC cell (T-MDSC) induction with IL-6 blocking. We identified that T-MDSCs promoted NPC cell migration and invasion by triggering the epithelial-mesenchymal transition (EMT) on cell-to-cell contact, and T-MDSCs enhanced tumor experimental lung metastasis in vivo. Interestingly, the contact between T-MDSCs and NPC cells enhanced tumor COX-2 expression, which subsequently activated the ß-catenin/TCF4 pathway, resulting in EMT of the cancer cells. Blocking transforming growth factor ß (TGFß) or inducible nitric oxide synthase (iNOS) significantly abolished the T-MDSC-induced upregulation of COX-2 and EMT scores in NPC cells, whereas the administration of TGFß or L-arginine supplements upregulated COX-2 expression and EMT scores in NPC cells. These findings reveal that COX-2 is a key factor mediating the interaction between MDSCs and tumor cells, suggesting that the inhibition of COX-2 or MDSCs has the potential to suppress NPC metastasis.

Myeloid-derived suppressor cells inhibit T cell proliferation in human extranodal NK/T cell lymphoma: a novel prognostic indicator.

The expansion of myeloid-derived suppressor cells (MDSCs) and its correlation with advanced disease stage have been shown in solid cancers. Here, we investigated the functional features and clinical significance of MDSCs in extranodal NK/T cell lymphoma (ENKL). A higher percentage of circulating HLA-DR(-)CD33(+)CD11b(+) MDSCs was observed in ENKL patients than in healthy controls (P < 0.05, n = 32) by flow cytometry analysis. These MDSCs from ENKL patients (ENKL-MDSCs) consisted of CD14(+) monocytic (Mo-MDSCs, >60 %) and CD15(+) granulocytic (PMN-MDSCs, <20 %) MDSCs. Furthermore, these ENKL-MDSCs expressed higher levels of Arg-1, iNOS and IL-17 compared to the levels of MDSCs from healthy donors, and they expressed moderate levels of TGFß and IL-10 but lower levels of CD66b. The ENKL-MDSCs strongly suppressed the anti-CD3-induced allogeneic and autologous CD4 T cell proliferation (P < 0.05), but they only slightly suppressed CD8 T cell proliferation (P > 0.05). Interestingly, ENKL-MDSCs inhibited the secretion of IFNγ but promoted IL-10, IL-17 and TGFß secretion as well as Foxp3 expression in T cells. The administration of inhibitors of iNOS, Arg-1 and ROS significantly reversed the suppression of anti-CD3-induced T cell proliferation by MDSCs (P < 0.05). Importantly, based on multivariate Cox regression analysis, the HLA-DR(-)CD33(+)CD11b(+) cells and CD14(+) Mo-MDSCs were independent predictors for disease-free survival (DFS, P = 0.013 and 0.016) and overall survival (OS, P = 0.017 and 0.027). Overall, our results identified for the first time that ENKL-MDSCs (mainly Mo-MDSCs) have a prognostic value for patients and a suppressive function on T cell proliferation.

Tumor-induced myeloid-derived suppressor cells promote tumor progression through oxidative metabolism in human colorectal cancer.

BACKGROUND: Expansions of myeloid-derived suppressor cells (MDSCs) have been identified in human solid tumors, including colorectal cancer (CRC). However, the nature of these tumor-associated MDSCs and their interactions with tumor cells in CRC are still poorly understood. METHODS: The percentages and phenotype of MDSCs in peripheral blood and tumorous and paraneoplastic tissues from CRC patients, as well as the clinical relevance of these MDSCs, were assessed. Age-matched healthy donors were included as controls. The interaction between MDSCs and T cells or tumor cells was investigated in a coculture system in vitro, and the molecular mechanism of the effect of MDSCs on T cells or tumor cells was evaluated. RESULTS: We discovered that CRC patients had elevated levels of CD33(+)CD11b(+)HLA-DR(-) MDSCs in primary tumor tissues and in peripheral blood, and the elevated circulating MDSCs were correlated with advanced TNM stages and lymph node metastases. Radical resection significantly decreases the proportions of circulating MDSCs and CD4(+)CD25(high)FOXP3(+) regulatory T cells. In vitro, CRC cells mediate the promotion of MDSC induction. Moreover, these tumor-induced MDSCs could suppress T cell proliferation and promote CRC cell growth via cell-to-cell contact. Such effects could be abolished by the inhibition of oxidative metabolism, including the production of nitric oxide (NO), and reactive oxygen species (ROS). CONCLUSIONS: Our results reveal the functional interdependence between MDSCs, T cells and cancer cells in CRC pathogenesis. Understanding the impact of MDSCs on T cells and tumor cells will be helpful to establish an immunotherapeutic strategy in CRC patients.